Ramadan et al. Head & Neck Oncology 2012, 4:39 http://www.headandneckoncology.org/content/4/1/39
PUBLISHER’S NOTE: Based on the information available to BioMed Central, this article was apparently handled by Waseem Jerjes, an author of the article and Editor-in-Chief of the journal at that time. The manuscript was reviewed by two recent co-authors of Waseem Jerjes and accepted without revision.
RESEARCH
Open Access
Spinal metastasis in thyroid cancer Sami Ramadan1, Mohamed A Ugas2, Richard J Berwick1, Manisha Notay1, Hyongyu Cho2, Waseem Jerjes3,4,5,6* and Peter V Giannoudis5,6* Abstract Background: Thyroid carcinoma generally responds well to treatment and spinal metastasis is an uncommon feature. Many studies have looked at the management of spinal metastasis and proposed treatments, plans and algorithms. These range from well-established methods to potentially novel alternatives including bisphosphonates and vascular endothelial growth factor (VEGF) therapy, amongst others. The purposes of this systematic review of the literature are twofold. Firstly we sought to analyse the proposed management options in the literature. Then, secondly, we endeavoured to make recommendations that might improve the prognosis of patients with spinal metastasis from thyroid carcinomas. Methods: We conducted an extensive electronic literature review regarding the management of spinal metastasis of thyroid cancer. Results: We found that there is a tangible lack of studies specifically analysing the management of spinal metastasis in thyroid cancer. Our results show that there are palliative and curative options in the management of spinal metastasis, in the forms of radioiodine ablation, surgery, selective embolisation, bisphosphonates and more recently the VEGF receptor targets. Conclusions: The management of spinal metastasis from thyroid cancer should be multi-disciplinary. There is an absence; it seems, of a definitive protocol for treatment. Research shows increased survival with 131I avidity and complete bone metastasis resection. Early detection and treatment therefore are crucial. Studies suggest in those patients below the age of 45 years that treatment should be aggressive, and aim for cure. In those patients in whom curative treatment is not an option, palliative treatments are available.
Introduction Thyroid cancer is uncommon, accounting for roughly 1% of all new malignant disease, about 05% of cancers in men and 15% in women [1-4]. It affects approximately 1900 people in the UK each year, but its incidence has been increasing for decades [5-8]. Much of the rise in incidence can be explained by improved diagnostic methods. However, this cannot entirely explain the upward trend [8-10]. Differentiated thyroid cancer (DTC) account for the vast majority (90%) of all thyroid cancers and includes papillary (70–75%) and follicular (15–20%) cancers. Hürthle-cell cancers (2%) and insular carcinomas also arise from follicular cells but are probably within the spectrum from differentiated to undifferentiated. * Correspondence:
[email protected];
[email protected] 3 Department of Surgery, Al-Yarmouk University College, Baghdad, Iraq 5 Leeds Institute of Molecular Medicine, University of Leeds, London, UK Full list of author information is available at the end of the article
Undifferentiated carcinomas, which are anaplastic malignancies, account for 0.007). Pamidronate was also effective at pain amelioration [45], with a 31.35% reduction using the VAS scoring. Patient tolerability was good, although the side effect of osteonecrosis of the jaw is, unfortunately, relatively high at 9% [15], though the study size was small. Other studies have intimated that as much as 5% of the oncological patients receiving bisphosphonate therapy for ~4.4 years develop bisphosphonate-related osteonecrosis of the jaw (BRONJ) [52]. The authors reported an impressive spinal cord compression reduction, although study size was small (n = 28). Small molecules
The effect of small molecule inhibitors has revolutionised the treatment of some cancers, and the search of molecular targets in neoplasm continues. Growth signaling
pathways are implicated in tumorigenesis, especially those of angiogenesis. Vascular endothelial growth factor receptors (VEGFR) inhibitors appear not to improve progression free survival in metastatic thyroid cancer [37]. However, small study sizes have impeded research. In a study by Kloos et al. [37], side effects prompted 52% of patients to reduce their dose. Cabanillas et al. [35], treated 15 patients, mostly with non 131I avid disease with different VEGFR inhibitors, notably sorafenib. Interestingly, progression free survival was increased. It was observed that patients whom had their SM irradiated, prior to VEGF therapy, maintained stable bone disease, whereas those who did not have irradiation experienced rapid progression, despite a good response of their lung metastasis to VEGF therapy. This raises the possibility that treating patients with (external bean radiation therapy) EBRT prior to VEGF therapy could improve survival. This may need to be examined in further detail. Difficulties encountered
We encountered difficulties with regards to study selection and data extraction, contemporaneous research, study size and consistency of protocol. We cannot claim to have used a complete and exhaustive list of studies. Our search results yielded a large body of research relevant to our
Ramadan et al. Head & Neck Oncology 2012, 4:39 http://www.headandneckoncology.org/content/4/1/39
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Figure 3 The proposed recommendations of treatment.
title. We cross-examined the references to add to this body. This approach is rigorous but not consummate. In addition, many of the papers made analysis difficult due to the presentation of their data. Spinal metastasis was rarely isolated as a subgroup. Indeed, many forms of metastases were pooled for the statistics. It was, therefore, impossible to extract specific and valuable information from these studies [35,37,46]. Several retrospective studies did not use contemporary data sets. Studies, recruited by the inclusion criteria, analysed investigation and treatment modalities in a patient pool, which was considerably dated due to some cohorts having been accrued over decades. These studies spanned a long period of time, during which, treatment
and investigative modalities had significantly evolved. They, therefore, encompassed a number of out-dated clinical practices and ignored currently well-established modalities [29,30,34,42]. Much of the literature on spinal metastasis in thyroid cancer is based on small sample sized studies. This makes it difficult to measure the effectiveness of some treatment modalities and draw conclusions. Additionally, this makes it difficult to use the data in multivariate analysis due to the high standard errors, which would occur with small sample size [14,16,36,40,44,45]. Finally, most countries have specific guidelines and recommendations for the management of certain cancers, including the UK [19]. It was difficult to make
Ramadan et al. Head & Neck Oncology 2012, 4:39 http://www.headandneckoncology.org/content/4/1/39
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recommendations when papers preconised the use of different ‘successful’ methods in similar situations. This applied to certain treatments, such as thyroidectomy, or to dose, such of 131I used [14,16,19,40].
and lymphangiogenic phenotypes, spread to the vertebral column is poorly understood. Dissection of this journey opens the possibility of intervening to improve patient survival and reduced morbidity.
Recommendations
Conclusions There is a need for more histology-specific research in the field of thyroid carcinoma metastasis. While study sizes are difficult to control, we believe that there is room for improvement in study design and in the quantity of research on specific treatment modalities. To sum up, for a young patient aggressive surgery is the best first line management. Radioiodine and surgery is our best combined management. Combination therapy, SET or small molecular inhibitor with radiation is recommended. Furthermore, VEGFR is particularly helpful in 131I non-avid disease. SET and bisphosphonates are useful modalities in palliation. However, more research is required into the effect of combination therapies. Future prospects look towards intersecting the molecular pathways of tumourigenesis and dissemination. Indeed, spread to the spine is haematogenous, which opens an avenue to pursue. At present, surgery is our most logical solution, but it certainly is not curative, but, rather, symptom control. Cure is the aim.
Individual prognosis depends upon age at diagnosis of spinal metastasis, tumour burden and number of spinal metastases [29,30,34,42,47]. Early detection is a prognostic factor in spinal metastasis of differentiated thyroid carcinoma (DTC). This early detection could help prevent dissemination to the spine. The proposed process of which is outlined in figure 2. Post-surgical 131I ablation, in addition to adjuvant therapy, has been shown to aid in the early detection of bone metastasis. At this time, thyroglobulin levels are low, and radiological studies are often negative [14]. Treatment of metastasis should be done in a multi-disciplinary fashion and take into account tumour response, palliation and neurological function. Recommendations of treatment are illustrated in Figure 3. Radioiodine absorption is a prognostic factor in metastatic disease. Multivariate analysis expounds the prognostic benefit of complete metastectomy and 131Itherapy, when applicable. Survival rates in DTC patients are improved by these interventions [13,34,38,47]. This is, especially so in those below the age of 45, in whom bone is the only distant metastasis [34]. We espouse that therapy should be aggressive, particularly in the young [34]. Patients below the age of 45 years of age with small DTC distant metastasis should be treated with radioiodine until there is an uptake decline or a cumulative dose of 600 mCi (22 GBq) reached [30]. Subsequent courses of radioiodine treatment, at least one year after initial radioiodine treatment may also be a recommended. Radioiodine therapy comes with its limitations, however. Treatment exceeding 600 mCi may be deleterious to the health. There is a significant increase in salivary gland dysfunction, cancer and leukaemia in patients. In patients with continued uptake, a decision to continue treatment beyond that dose should be considered on a case-by-case basis, due the risks associated [30]. In patients with non 131I avid disease, or who are 131I non-responders, other treatment modalities ought to be evaluated. Such treatments include combination therapy, SET or small molecules, along with radiotherapy. These may assuage symptomatic disease. VEGFR is particularly helpful in 131I non-avid disease. SET and bisphosphonates are especially useful modalities in reducing bone pain [15,16,44,45]. Thyroid cancer pathogenesis and promulgation to the bone has yet to be fully elucidated despite some novel research by Torre et al. [53] into the role of angiogenic
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